Cancer-associated fibroblast-derived ANP32A drives cisplatin resistance in esophageal squamous cell carcinoma

ABSTRACT: Cisplatin resistance is a major barrier to effective treatment of esophageal squamous cell carcinoma (ESCC), yet the metabolic contributions of stromal cells to this phenotype remain incompletely defined. Here, we demonstrate that cancer-associated fibroblasts (CAFs) elevate glutathione (GSH) abundance and reduce the oxidative vulnerability of ESCC cells through extracellular vesicle (EV)-mediated communication. Proteomic profiling of CAF-derived EVs, combined with prognostic analysis, identified acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A) as a candidate effector. Genetic depletion of ANP32A in CAFs impaired the capacity of their EVs to upregulate GSH, suppress reactive oxygen species (ROS) and lipid peroxidation, and protect ESCC cells from cisplatin-induced cytotoxicity. Mechanistically, ANP32A interacted with annexin A2 (ANXA2) and STAT3, and this interaction was required for efficient STAT3 activation. ChIP-based analyses identified the SLC29A4 gene, which encodes plasma membrane monoamine transporter (PMAT), as a downstream STAT3 target gene essential for ANP32A-dependent GSH homeostasis and cisplatin resistance. Deletion mapping further pinpointed amino acids 123-161 of ANP32A as the region required for efficient ANXA2 association and the full drug-resistant phenotype. Finally, tumor-targeted tetrahedral DNA nanostructures delivering siANP32A reduced GSH levels, increased lipid peroxidation, and suppressed the growth of ESCC xenografts. These findings uncover a stromal EV-protein-dependent pathway that links intercellular communication to redox adaptation and cisplatin resistance in ESCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE351727 | GEO | 2026/10/25

REPOSITORIES: GEO